Patients with hepatitis B virus infection were excluded from the discovery cohort, as well as from the replication cohorts. A second, independent cohort of Caucasian patients with chronic HCV infection with or without HCC was identified (designated as Berlin/Bonn selleck chemicals llc cohort in the following); these patients were recruited at the University Hospital Departments of Gastroenterology and Hepatology in Bonn, Berlin and Leipzig in Germany, as described in Nischalke et al [12]. In addition, two independent cohorts of Japanese patients with chronic hepatitis C with or without HCC were included (a detailed description of these cohorts is provided in Miki et al. [4]; the cohorts are designated as Japanese GWAS and Japanese Replication cohort, as in Miki et al.).

Importantly, the duration of infection with HCV was known in patients of the SCCS but not in the three additional cohorts. In addition to the primary analysis of this study, a number of sub-analyses were performed in order to validate our research strategy. These sub-analyses investigated possible associations between genetic variations in CYP2R1, GC and DHCR7 and i) liver fibrosis progression rate (FPR), ii) response to treatment with pegylated interferon-�� (PEG-IFN-��) and ribavirin, and iii) 25(OH)D3 serum levels. These sub-analyses were performed in SCCS patients only because of the thorough documentation of these end-points together with the known duration of infection in the SCCS. FPR was defined as a dichotomized phenotype (< vs.

�� sex-adjusted median FPR), which was calculated on the basis of the ratio of the METAVIR fibrosis score to the estimated duration of infection in years until liver biopsy (METAVIR units per year), as described previously [13]. Hence, all SCCS patients with at least one available liver biopsy with fibrosis staging prior to antiviral treatment and with known date of infection were included in the analyses of FPR. The treatment response analyses was restricted to SCCS patients who were treated under clinical practice conditions with either PEG-IFN-��2a or PEG-IFN-��2b in combination with weight-based ribavirin, with standard treatment durations (48 weeks for HCV genotype 1 and 4, 24 weeks for HCV genotype 2 and 3), and if they had received ��80% of the recommended dose of both agents during the first 12 weeks of therapy.

SVR was defined as HCV RNA below the limit of detection in a sensitive assay ��24 weeks after treatment completion, and all patients who failed to achieve SVR were classified as nonresponders. Serum concentrations of 25(OH)D3 were determined in all SCCS patients with chronic hepatitis C in whom a plasma sample at baseline of antiviral Cilengitide therapy or at the time of a liver biopsy was available. Demographic and clinical characteristics were extracted from clinical databases. High alcohol intake was defined as consumption >40 g per day over a period of ��5 years. Liver biopsies were evaluated by experienced local pathologists.